CN107850564B - System and method for being detected in ion fluid - Google Patents

System and method for being detected in ion fluid Download PDF

Info

Publication number
CN107850564B
CN107850564B CN201680024582.4A CN201680024582A CN107850564B CN 107850564 B CN107850564 B CN 107850564B CN 201680024582 A CN201680024582 A CN 201680024582A CN 107850564 B CN107850564 B CN 107850564B
Authority
CN
China
Prior art keywords
electrode
grid
field effect
effect transistor
target
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201680024582.4A
Other languages
Chinese (zh)
Other versions
CN107850564A (en
Inventor
熊乐昌
戴君彦
陈育琳
林芳瑜
C·W·E·胡
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beth El Polytron Technologies Inc
Original Assignee
Beth El Polytron Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beth El Polytron Technologies Inc filed Critical Beth El Polytron Technologies Inc
Publication of CN107850564A publication Critical patent/CN107850564A/en
Application granted granted Critical
Publication of CN107850564B publication Critical patent/CN107850564B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502753—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/72—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood pigments, e.g. haemoglobin, bilirubin or other porphyrins; involving occult blood
    • G01N33/721—Haemoglobin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0636—Integrated biosensor, microarrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/087—Multiple sequential chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883—Serpentine channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/088—Passive control of flow resistance by specific surface properties
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay

Abstract

The present invention provides a kind of system (300) and method to detect target (324), for being detected in ion fluid, wherein, electric chemical formula extends gridistor (electrochemical extended-gate transistor；EET) system includes: field effect transistor (field effect transistor；FET) (310), with grid (312), source electrode (316) and drain electrode (314)；Potentiostat (330), with working electrode (332), to electrode (334) and reference electrode (336)；Wherein, the working electrode (332) and detection region (320) couple, and this couples electrode (334) and the grid (312)；Wherein, the detection region (320), the grid (312) and the reference electrode (336) are placed in ion fluid (302)；Wherein, which is configured, and redox reaction is generated in the ion fluid (302) with electrochemical method, and then detect the target (324).

Description

System and method for being detected in ion fluid
Technical field
The present invention relates to field effect transistor tubular type (field effect transistor-based；FET-based) biological Sensor, it is brilliant more particularly, to the field-effect for improving the detecting limit in macroion fluid and sensitivity using electrochemical method Body tubular type biological sensor.
Background technique
In diagnosis, determine that substance contained in blood or serum sample (such as protein or certain particular targets) is Important.For example, as shown in Fig. 1 (A), in general field effect transistor tubular type biological sensor 100, in order to detect specific life Substance markers (biomarker) 154 can be modified antibody or certain recognition components 152 on grid 150.When biomarker 154 is known When other element 152 captures, the charge of biomarker 154 be will build up in gate surface, to form current potential on grid 150, into And in the case where providing voltage source 110, through detecting flow through source electrode 140 and drain electrode 130 between substrate 120 electric current ( It is exactly IDS), it may be determined that the concentration of biomarker.
But, if test sample has high ionic strength, the current potential as caused by the charge of biomarker will be by sample In ion neutralize.In this way, once the distance between gate surface and the biomarker captured (r) are (such as more than specific length Fig. 1 (B)), that is, Debye length (Debye length) (λ), ion in sample can the captured biomarker of mask electricity Position.May be decreased by the current potential of mask flow through source electrode 140 and drain electrode 130 between substrate 120 electric current, and then prevent system from Detecting limit and sensitivity needed for enough offers are used to detect the concentration of biomarker.
Therefore, traditional field effect transistor biological sensor can not provide the target for detecting in macroion fluid (ionic strength is~150mM for detecting limit needed for biomarker and sensitivity；Such as table 1).Fig. 2 is further illustrated in 100mM Phosphate buffer solution (phosphate buffer solution；PBS) (ionic strength is~400mM；Such as table 1) and 0.1mM (ionic strength is~0.4mM to PBS；Such as table 1) in traditional extension gate field effect transistor (extended-gate field effect transistor；EGFET the comparison of detecting result).Therefore, because the reduction of Debye length, in macroion fluid The lower ion fluid of detecting limit in detecting limit it is poor.Table 1 is please referred to, in 100mM PBS, Debye length can be further Be reduced to~0.48nm, the Debye length be less than hemoglobin diameter (~5nm, Biol Proced Online 2009,11: 32-51).Therefore, the contained charge of hemoglobin be not enough on the grid of extension gate field effect transistor generate current potential and Cause corresponding IDSTo be detected.
The various methods for such detecting have been disclosed in document.For example, about the macroion stream as shown in Fig. 1 (B) Sample in body, Part Methods are to extend Debye length through the test sample is diluted to reach low ionic strength state.No It crosses, by this method, measuring condition will be limited significantly and will be not used in practical application, such as to the target organism of low concentration Label is made to limit caused by further dilution.In another approach, to remove the ion in test sample, test sample must The pretreatment process of multiple complexity must be passed through, these processes will consume more times and cost.Electrochemistry (electrochemical；EC) system can pass through detecting electrochemical signals as Debye length solution to the problem is solved. But, when target concentration is low, the sensitivity of Conventional electrochemical system is insufficient.
Therefore, industry needs to overcome the problems, such as on these traditional technologies.
Summary of the invention
The present invention provides electrochemistry extension gate field effect transistor formula system, and it is brilliant to extend grid for also referred to as electric chemical formula Body pipe (electrochemical extended-gate transistor；EET) system can be avoided asking for Debye length Topic simultaneously can be directly to detect the target (for example, biomarker) in macroion fluid.In addition, Applied Electrochemistry method of the present invention Extend in gate transistors guard system in electric chemical formula, and then can pass through detecting and generated in ion fluid because of redox reaction Electrochemical signals to determine the concentration of target.
Extend gate transistors guard system, the electric chemical formula to detect the electric chemical formula of target provided by according to the present invention Extending gate transistors guard system includes: field effect transistor (field effect transistor；FET), with grid, Source electrode and drain electrode；Potentiostat, with working electrode, to electrode and reference electrode；Wherein, the working electrode and detecting Area's coupling, and this couples electrode and the grid；Wherein, the detection region, the grid and the reference electrode are placed in ion fluid In；Wherein, which is configured, and redox reaction is generated in the ion fluid with electrochemical method, and then detect The target.
In one embodiment, which includes reading unit coupled with it, to quantized signal.
In one embodiment, which can be for n-MOS, p-MOS field effect transistor or with similar functions Any element.
In one embodiment, formed the working electrode, to the substance of electrode and reference electrode include it is at least one from Substance selected by lower group: Au Ag Pt Pd, carbon, indium tin oxide (indium tin oxide；ITO) glass, any conduction Ink, or any combination thereof.
In one embodiment, which can be gaseous state or liquid.
In one embodiment, which can be electrolyte, such as PBS, blood, serum, urine, saliva, sweat, or Ionic strength and the approximate any solution of physiological environment.
In one embodiment, which includes at least one substance selected by the following group: small molecule, protein, enzyme, Antigen, nucleic acid, DNA, RNA, miRNA, is suitble to body (aptamer), glycolipid, dentate, excretion body (exosome) or appoints antibody Meaning can be used for sensing the biomarker of application.
In one embodiment, there is the recognition component of affinity or specificity to modify the detection region target.
In one embodiment, which can be any molecule to the target with affinity or specificity.
In one embodiment, which can be related to electrochemistry (electrochemical；EC) movable.
Moreover, the present invention also provides one kind to detect target calibration method, comprising: providing has grid, source electrode and drain electrode Field effect transistor；There is provided have working electrode, to the potentiostat of electrode and reference electrode, wherein the working electrode with Detection region coupling, wherein this couples electrode and the grid, wherein the detection region, the grid and the reference electrode be placed in from In subflow body；And the electrochemical method driven by the potentiostat is executed, to generate redox in the ion fluid Reaction, and then detect the target.
In the present invention, which includes: voltammetry, Amperometric, conductance method, impedance method or any conventional electricity Chemical method.
Detailed description of the invention
Fig. 1 (A) and 1 (B) is that be painted traditional field effect transistor tubular type biological sensor and ionic strength and debye long Relationship between degree；
Fig. 2 is to detect blood in 100mM PBS and 0.1mM PBS using traditional extension gate field effect transistor system The result of Lactoferrin；
Fig. 3 is the schematic diagram for extending gate transistors guard system according to the electric chemical formula of one embodiment of the invention, wherein arrow For example direction, to illustrate the direction of redox reaction；
Fig. 4 is the schematic diagram for extending gate transistors guard system according to the electric chemical formula of one embodiment of the invention, wherein to this Electric chemical formula extends gate transistors guard system and introduces recognition component and energy transmission medium (mediator)；
Fig. 5 (A) is according to one embodiment of the invention, by traditional blood red egg of extension gate field effect transistor systems scan The relational graph of white detecting time and standard galvanic current ratio；
Fig. 5 (B) is according to one embodiment of the invention, by traditional blood red egg of extension gate field effect transistor systems scan The relational graph of white hemoglobin concentration and standard galvanic current ratio；
Fig. 5 (C) is to extend gridistor systems scan hemoglobin by electric chemical formula according to one embodiment of the invention Detect the relational graph of time and standard galvanic current ratio；
Fig. 5 (D) is to extend gridistor systems scan hemoglobin by electric chemical formula according to one embodiment of the invention The relational graph of hemoglobin concentration and standard galvanic current ratio；
Fig. 6 (A) is according to one embodiment of the invention, by Conventional electrochemical systems scan H2O2The detecting time and standardization The relational graph of electric current ratio；
Fig. 6 (B) is according to one embodiment of the invention, by Conventional electrochemical systems scan H2O2H2O2Concentration and standardization The relational graph of electric current ratio；
Fig. 6 (C) is to extend gridistor systems scan H by electric chemical formula according to one embodiment of the invention2O2Detecting The relational graph of time and standard galvanic current ratio；
Fig. 6 (D) is to extend gridistor systems scan H by electric chemical formula according to one embodiment of the invention2O2H2O2 The relational graph of concentration and standard galvanic current ratio；
Fig. 7 be electric chemical formula of the invention extend gate transistors guard system and traditional extension gate field effect transistor and The comparison figure of the industrial value of electro-chemical systems.
Symbol description
100 general field effect transistor tubular type biological sensors
110 voltage source, 120 substrate
130 140 source electrodes of drain electrode
150 grid, 152 recognition component
154 biomarkers
300 electric chemical formulas extend gate transistors guard system
302 ion fluid, 310 field effect transistor
The drain electrode of 312 grids 314
316 source electrode, 320 detection region
324 target, 330 potentiostat
332 working electrodes 334 are to electrode
336 reference electrode, 340 reading unit
400 electric chemical formulas extend gate transistors guard system
402 ion fluid, 404 energy transmission medium
410 field effect transistor, 412 grid
414 416 source electrodes of drain electrode
420 detection region, 422 recognition component
424 target, 430 potentiostat
432 working electrodes 434 are to electrode
436 reference electrode, 440 reading unit.
Specific embodiment
Specific embodiment below to illustrate disclosure of the invention, read this specification disclosure with Afterwards, those skilled in the art can be readily understood upon its advantage and effect.
It should be clear that this specification structure depicted in this specification institute accompanying drawings, ratio, size etc., only cooperation specification is revealed Content so that those skilled in the art are able to understand and read, and is not intended to limit the invention among specified conditions, therefore not With technical essential meaning.The modification of any structure, the change of proportionate relationship or the adjustment of size, are not influencing this theory Under the effect of bright book can be generated and the purpose that can reach, it should be included in range disclosed by this specification.In no reality In the case where qualitative change more technology contents, relativeness is altered or modified, also when being considered as in the enforceable scope of the present invention.
Fig. 3 is the schematic diagram for extending gate transistors guard system according to the electric chemical formula of one embodiment of the invention.System 300 is wrapped It includes: field effect transistor (FET) 310, with grid 312, source electrode 316 and drain electrode 314；Potentiostat 330, with work Make electrode 332, to electrode 334 and reference electrode 336；Wherein, the working electrode 332 and detection region 320 couple, and this is to electricity Pole 334 and the grid 312 couple；Wherein, the detection region 320, the grid 312 and the reference electrode 336 are arranged at ion In fluid 302；Wherein, potentiostat 330 is used to generate redox reaction in ion fluid 302, and then with electrochemistry Method detects target 324.
Fig. 3 illustrates that electric chemical formula according to an embodiment of the invention extends the detecting mechanism of gate transistors guard system.For Detect target, it may include electrochemistry (EC) method that electric chemical formula, which extends gate transistors guard system 300, and working electrode 332 with it is right Voltage difference between electrode 334 will drive the target 324 in ion fluid 302 to carry out redox.In this method, field-effect Therefore the grid voltage of transistor 310 will be controlled by the voltage to electrode 334, to cause the electric current (I between Drain-SourceDS), The electric current can be read unit 340 and be detected.Therefore, the concentration of target 324 is able to the I that reading unit 340 is detectedDSCarry out table Show.In addition, certain targets 324 perhaps have specific electrochemical properties, when potentiostat 330 executes electrochemical method appropriate When, target 324 can produce corresponding faradic currents and a pair of of redox peak be presented when applying specific potential.It is more desirable Ground using to target 324 there is the recognition component (Fig. 3 is not shown) of specificity to extend gate transistors guard system to electric chemical formula 300 detection region 320 is modified.When more recognition components are combined with target 324, the characteristic signal of target 324 (such as exists The peak current of oxidation-reduction potential) it will also be measured.In addition, the signal can further be amplified by field effect transistor 310, in turn The concentration of target 324 is calculated and obtained through the reading unit 340 coupled with field effect transistor 310.
Fig. 4 shows that electric chemical formula according to another embodiment of the present invention extends gate transistors guard system 400.Hereinafter, at this In entire embodiment, similar element is indicated with similar number, and omit its repetitive description.It in this embodiment, is benefit With the detection region 420 that there is the recognition component 422 of specificity to extend gate transistors guard system 400 to electric chemical formula target 424 It is modified, and target 424 does not have electro-chemical activity.Due to target 424 can not generate enough redox currents with The detecting of target is carried out, therefore, in this embodiment, additional energy transfer medium 404 is added in ion fluid 402, to promote Into electric current caused by redox reaction.Energy transmission medium 404 can be any one usually used in the art Energy transmission medium, the such as, but not limited to potassium ferricyanide, ferrocene and tetrathiafulvalene (tetrathiafulvalene； TTF).When implementing electrochemical method, added energy transmission medium 404 can be driven to generate redox current.With this side Formula, when more recognition components 422 are combined with target 424, the impedance of detection region 420 will change, meanwhile, by energy transmission The redox current that medium 404 generates can also change correspondingly.By this method, the concentration of target 424 can pass through reading unit 440 Calculating is learnt.
An embodiment according to the present invention provides a kind of utilization electric chemical formula extension detecting target of gate transistors guard system 300 The method of mark 324 simultaneously illustrates in Fig. 3.This method comprises: providing has the field-effect of grid 312, source electrode 316 and drain electrode 314 brilliant Body pipe (FET) 310；There is provided has working electrode 332, the potentiostat 330 to electrode 334 and reference electrode 336；Wherein, should Working electrode 332 and detection region 320 couple, wherein this couples electrode 334 and the grid 312, wherein the detection region 320, The grid 312 and the reference electrode 336 are arranged in ion fluid 302；And it executes and is driven by potentiostat 330 Electrochemical method is able to generate redox reaction in ion fluid 302, and then detects target 324.
The present invention is through detail section for the example of embodiment.But, annotation of the invention should not be construed as being limited to following The elaboration of embodiment.
Embodiment 1:
Even if the implementation tested below can illustrate that electric chemical formula extends gate transistors guard system in physiological ionic strength environment In superior sensing performance (such as detecting limit and signal magnitude of reaction) can be also provided.In this embodiment, target is blood Lactoferrin.Potentiostat is CHI6192E (texas,U.S Austin CHI company), but other traditional potentiostats can also be used Or analogous instrument, and its working electrode, to electrode and reference electrode respectively with carbon electrode, carbon electrode and Ag/AgCl electrode Electric property coupling.In this embodiment, can those electrodes be applied with any suitable pre-treatment, for example, using oxygen plasma-based, ethyl alcohol or Deionized water cleaning.In addition, it will be appreciated by those skilled in the art that in the art, PBS is usually to simulate physiologic ring Border.The ion fluid of the present embodiment is 100mM PBS, utilizes 100mM Na2HPO4And 100mM NaH2PO4It prepares, and pH value It is 7.4.
Later, extend gridistor systematic survey from 0.01 μ g/ml to the blood red egg of 100 μ g/ml using electric chemical formula White solution concentration.In this measurement process, using Amperometric, and the voltage difference between working electrode and reference electrode is set as- 0.4V, to drive corresponding redox reaction.
It as a control group, is using traditional extension gate field effect transistor systems scan hemoglobin.Extension The configuration of gate field effect transistor system and detecting condition and above-mentioned electric chemical formula extend gate transistors guard system configuration and Detecting condition is identical.Source electrode measuring unit, but source electrode measuring unit are also used in extension gate field effect transistor system Only to provide current potential and measuring signal relative to reference electrode.
Gate transistors guard system is extended by traditional extension gate field effect transistor system and electric chemical formula of the invention The measurement result of detecting is shown in Fig. 5.Refer to time of measuring in Fig. 5 (A) and 5 (C), x-axis, and in Fig. 5 (B) and 5 (D), x-axis is Refer to the concentration of hemoglobin.Y-axis refers to electric current ratio, Δ IDS(variation of drain-source current flow)/I0(in not hemoglobin The electric current detected in PBS).The ratio of electric current shown in y-axis (Δ IDS/I0) to illustrate normalised detecting result, so that this Field technical staff is readily appreciated that advantage and effect brought by the present invention.
Fig. 5 (A) and 5 (B) are clearly shown, and when the concentration of hemoglobin is equal to or less than 1 μ g/ml, use extension Formula gate field effect transistor systematic survey, can not observe signal.In addition, traditional extension gate field effect transistor system Detection signal (referring to electric current ratio) in 100 μ g/ml hemoglobins only higher than the detection signal of not hemoglobin 2% to 3%.
Conversely, according to Fig. 5 (C) and 5 (D), which illustrates electric current than the relevance between hemoglobin concentration.This Outside, electric chemical formula extends detecting limit of the detecting limit than extension gate field effect transistor system of gate transistors guard system At least improve 30 times, and reconnaissance range is the hemoglobin that~0.3 μ g/ml is extended to from the hemoglobin of 100 μ g/ml.Again Person, when the concentration of hemoglobin increases by 10 times, signal ratio (the Δ I that is detectedDS/I0) it is to increase~3% with linear relationship.
Embodiment 2:
The implementation tested below can illustrate that compared with Conventional electrochemical system, electric chemical formula extends gate transistors guard system and mentions For superior sensing performance.In this embodiment, sensing target is H2O2.Commercially available electrode test piece is used in this embodiment (DEP-ER-P, Japanese BioDevice company), wherein the working electrode of the electrode test piece distinguishes electrode and reference electrode It is made of gold, carbon and Ag/AgCl.Potentiostat is CHI6192E (texas,U.S Austin CHI company).In this embodiment Ion fluid is PBS (100mM Na2HPO4And 100mM NaH2PO4；pH 7.4).Before measuring, using ethyl alcohol and deionized water The electrode test piece is cleaned, and uses nitrogen drying.
Later, extend H of the gridistor systematic survey from concentration 1nM to 100 μM using electric chemical formula2O2Solution.Herein In measurement process, it is set as 0.25V using Amperometric, and by the voltage difference between working electrode and reference electrode, it is opposite to drive The redox reaction answered.The detecting environment of electro-chemical systems and aforementioned electric chemical formula extend the detecting ring of gate transistors guard system Border is similar.
The measurement result that gate transistors guard system is detected is extended by Conventional electrochemical system and electric chemical formula of the invention It is shown in Fig. 6.In Fig. 6 (A) and 6 (B), Δ ICWIt indicates to the curent change between electrode and working electrode.The results show that working as H2O2 Concentration when being equal to or less than 1 μM, the signal detected is unrecognizable.More specifically, detecting limit is 10 μM.
Conversely, according to Fig. 6 (C) and 6 (D), which illustrates electric current ratio and H2O2Relevance between concentration.In addition, The detecting limit that electric chemical formula extends gate transistors guard system at least improves 100 times than the detecting limit of electro-chemical systems, and detects It surveys range and is exaggerated to 100 μM to 0.1 μM H2O2。
Above explanation and embodiment clearly indicates that electric chemical formula of the invention extends gate transistors guard system institute energy band The advantage and effect come.More specifically, electric chemical formula of the invention extends gate transistors guard system and can pass through in the system Its signal detected is further amplified in the configuration of field effect transistor.As shown in table 2, the invention shows of the invention Electric chemical formula, which extends gate transistors guard system, can not only improve the moral of the extension gate field effect transistor in macroion fluid Length limitation is visitd, sensitivity of electrochemistry measurement in the case where low concentration can also be increased.In addition, through energy transmission is used Medium, no matter whether target has electro-chemical activity, and electric chemical formula extension gate transistors guard system of the invention all can measure should The concentration of target, and then more elasticity are provided in terms of detecting.In conclusion the present invention successfully provides electric chemical formula extension Gridistor detecting system, the system provide superior sensitivity and are done well in macroion fluid.Such as Fig. 7 institute Show, compared to extension gate field effect transistor system and electro-chemical systems, the present invention has higher in sensing application aspect Value.
The present invention only transmits the example of embodiment to illustrate, to show the principle of the present invention and effect, and not intended to limit The present invention.Those skilled in the art can make numerous variations and modification without departing from spirit and scope of the present invention to the present invention.Cause This, the scope of the present invention-scope of the claims is listed in herein.So the scope of the present invention should be by appended power Sharp claimed range definition.

Claims (18)

1. a kind of system to detect target, it is characterized in that, which includes:
Field effect transistor (FET), with grid, source electrode and drain electrode, wherein the field effect transistor is extension grid Field effect transistor；
Potentiostat, with working electrode, to electrode and reference electrode；
Wherein, the working electrode and detection region couple and the not direct and grid couples and by ion fluid and extension grid Coupling, and this couples electrode and the extension grid；
Wherein, the detection region, the extension grid and the reference electrode are placed in the ion fluid；
Wherein, which is configured, and redox reaction is generated in the ion fluid with electrochemical method, and then detect Target；
Wherein, the grid voltage of the field effect transistor is controlled by the voltage to electrode, and the voltage root to electrode Change according to the concentration of the target.
2. system according to claim 1, it is characterized in that, which includes reading unit coupled with it, To quantify measurement signal.
3. system according to claim 1, it is characterized in that, which is related to electrochemical activity.
4. system according to claim 1, it is characterized in that, which includes at least one object selected by the following group Matter: small molecule, protein, nucleic acid and glycolipid and any combination thereof.
5. system according to claim 1, it is characterized in that, which is liquid.
6. system according to claim 5, it is characterized in that, the ion fluid of the liquid is electrolyte.
7. system according to claim 1, it is characterized in that, which includes energy transmission medium.
8. system according to claim 1, it is characterized in that, to have the recognition component of affinity or specificity to the target Modify the detection region.
9. system according to claim 1, it is characterized in that, which is at least one selected by the following group Method, the group are made of voltammetry, Amperometric, conductance method, impedance method and any combination thereof.
10. a kind of method to detect target, it is characterized in that, this method comprises:
There is provided has grid, source electrode and the field effect transistor of drain electrode (FET), wherein the field effect transistor is extension grid Pole field effect transistor；
There is provided has working electrode, to the potentiostat of electrode and reference electrode, wherein the working electrode and detection region couple and It is not direct to couple with the grid and coupled by ion fluid and extension grid, wherein this is to electrode and the extension grid Coupling, wherein the detection region, the extension grid and the reference electrode are placed in the ion fluid；
The electrochemical method driven by the potentiostat is executed, redox reaction, Jin Erzhen are generated in the ion fluid Survey the target；And
Wherein, the grid voltage of the field effect transistor is controlled by the voltage to electrode, and the voltage root to electrode Change according to the concentration of the target.
11. according to the method described in claim 10, it is characterized in that, this method further comprise penetrate and the field effect transistor The reading unit of coupling quantifies the signal generated by the target by redox reaction.
12. according to the method described in claim 10, it is characterized in that, which is related to electrochemical activity.
13. according to the method described in claim 10, it is characterized in that, which includes at least one object as selected by following group Matter: small molecule, protein, nucleic acid and glycolipid and any combination thereof.
14. according to the method described in claim 10, it is characterized in that, the ion fluid be liquid.
15. according to the method for claim 14, it is characterized in that, the ion fluid of the liquid is electrolyte.
16. according to the method described in claim 10, it is characterized in that, which further includes energy transmission medium.
17. according to the method described in claim 10, it is characterized in that, to have the identification member of affinity or specificity to the target Part modifies the detection region.
18. according to the method described in claim 10, it is characterized in that, which is at least one selected by the following group Method, which is made of voltammetry, Amperometric, conductance method, impedance method and any combination thereof.
CN201680024582.4A 2015-04-30 2016-04-29 System and method for being detected in ion fluid Active CN107850564B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562155150P 2015-04-30 2015-04-30
US62/155,150 2015-04-30
PCT/CN2016/080679 WO2016173542A1 (en) 2015-04-30 2016-04-29 System and method for detection in ion fluid

Publications (2)

Publication Number Publication Date
CN107850564A CN107850564A (en) 2018-03-27
CN107850564B true CN107850564B (en) 2019-07-16

Family

ID=57198120

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201680024573.5A Pending CN107709990A (en) 2015-04-30 2016-04-29 For detecting the system and method for biomarker
CN201680024582.4A Active CN107850564B (en) 2015-04-30 2016-04-29 System and method for being detected in ion fluid

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201680024573.5A Pending CN107709990A (en) 2015-04-30 2016-04-29 For detecting the system and method for biomarker

Country Status (6)

Country Link
US (2) US9884320B2 (en)
EP (1) EP3274700A4 (en)
JP (1) JP2018515792A (en)
CN (2) CN107709990A (en)
TW (2) TWI635907B (en)
WO (2) WO2016173542A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11480567B2 (en) * 2017-02-15 2022-10-25 New Jersey Institute Of Technology Enhanced sensitivity and specificity for point-of-care (POC) micro biochip
CN110337586B (en) * 2017-02-22 2023-03-10 豪夫迈·罗氏有限公司 Analyte detector for detecting at least one analyte in at least one fluid sample
TWI671397B (en) * 2017-07-14 2019-09-11 國立中興大學 Granular body extraction device
CN108828046A (en) * 2018-04-23 2018-11-16 海南聚能科技创新研究院有限公司 A kind of COD real-time detector
CN112203581A (en) 2018-05-30 2021-01-08 美梦有限公司 Monitoring method and buffer structure
KR102345695B1 (en) * 2020-04-13 2021-12-31 한국전자기술연구원 Bio sensor using fet element and extend gate, and operating method thereof
CN113005021B (en) * 2020-06-17 2023-12-08 山东大学 Microfluidic chip and method for exosome cracking and detection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200521432A (en) * 2003-12-18 2005-07-01 Univ Chung Yuan Christian The ion sensor of extended-gate ion sensitive field effect transistor (EGFET) used to be as potassium ion and sodium ion sensor
CN101430303A (en) * 2007-11-07 2009-05-13 中国科学院电子学研究所 Single-layer functional film urease biologic sensor chip and production method thereof
CN101915799A (en) * 2010-07-15 2010-12-15 长沙理工大学 Extended grid field effect transistor sensing chip for detecting DNA molecules

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5200051A (en) * 1988-11-14 1993-04-06 I-Stat Corporation Wholly microfabricated biosensors and process for the manufacture and use thereof
US20060263888A1 (en) * 2000-06-02 2006-11-23 Honeywell International Inc. Differential white blood count on a disposable card
US20040126814A1 (en) * 2000-08-21 2004-07-01 Singh Waheguru Pal Sensor having molecularly imprinted polymers
US20040018611A1 (en) * 2002-07-23 2004-01-29 Ward Michael Dennis Microfluidic devices for high gradient magnetic separation
TWI281500B (en) * 2003-12-31 2007-05-21 Univ Nat Yunlin Sci & Tech Penicillin g biosensor, systems comprising the same, and measurement using the systems
AU2005218622A1 (en) * 2004-03-03 2005-09-15 Living Microsystems Magnetic device for isolation of cells and biomolecules in a microfluidic environment
WO2006052891A1 (en) * 2004-11-09 2006-05-18 The Regents Of The University Of California Analyte identification using electronic devices
CN1786710B (en) 2004-12-06 2011-12-14 财团法人工业技术研究院 Microfluid chip for testing analysing body and its method
JP4081477B2 (en) * 2005-03-29 2008-04-23 株式会社日立製作所 Biomolecule detection apparatus and biomolecule detection method using the same
US20070000778A1 (en) * 2005-06-30 2007-01-04 Chung Yuan Christian University Multi-parameter sensor with readout circuit
KR20080074119A (en) * 2005-11-09 2008-08-12 코닌클리케 필립스 일렉트로닉스 엔.브이. Device for testing a fluid
US20070122819A1 (en) * 2005-11-25 2007-05-31 Industrial Technology Research Institute Analyte assay structure in microfluidic chip for quantitative analysis and method for using the same
TWI302197B (en) * 2006-01-04 2008-10-21 Univ Nat Yunlin Sci & Tech Reference ph sensor, the preparation and application thereof
KR100773550B1 (en) * 2006-04-03 2007-11-07 삼성전자주식회사 Method of detecting bio-molecules using field effect transistor without fixing bio-molecules
WO2009002580A2 (en) 2007-04-02 2008-12-31 Boston Medical Center Corporation Method for bacterial lysis
EP2160612A4 (en) * 2007-05-23 2016-04-27 Univ Arizona Systems and methods for integrated electrochemical and electrical detection
CN101256167B (en) * 2008-04-17 2011-11-23 重庆大学 Reading circuit of micro-array biosensor
EP2315848B1 (en) * 2008-07-18 2014-12-10 Canon U.S. Life Sciences, Inc. Methods and systems for microfluidic dna sample preparation
KR101140049B1 (en) * 2010-03-23 2012-05-02 서울대학교산학협력단 A High-Performance VEGF Aptamer Funtionalized Polypyrrole Nanotube Biosensor
KR101287162B1 (en) * 2010-03-31 2013-07-17 서울대학교산학협력단 Reference potential controlling equipment and measuring device including the same
WO2012040493A2 (en) * 2010-09-22 2012-03-29 California Institute Of Technology A lateral flow microfluidic assaying device and related method
US9518953B2 (en) * 2011-09-07 2016-12-13 Technion Research And Development Foundation Ltd. Ion sensitive detector
JP5447716B1 (en) * 2013-04-30 2014-03-19 国立大学法人 東京大学 Biosensor and molecular identification member

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200521432A (en) * 2003-12-18 2005-07-01 Univ Chung Yuan Christian The ion sensor of extended-gate ion sensitive field effect transistor (EGFET) used to be as potassium ion and sodium ion sensor
CN101430303A (en) * 2007-11-07 2009-05-13 中国科学院电子学研究所 Single-layer functional film urease biologic sensor chip and production method thereof
CN101915799A (en) * 2010-07-15 2010-12-15 长沙理工大学 Extended grid field effect transistor sensing chip for detecting DNA molecules

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemistry integrated circuit: chemical system on a complementary metal oxide semiconductor integrated circuit;Kazuo Nakazato;《PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES》;20140328;第372卷(第2012期);全文 *
Study on extended gate field effect transistor with tin oxide sensing membrane;Chi Lilun等;《MATERIALS CHEMISTRY AND PHYSICS》;20000214;第63卷(第1期);全文 *

Also Published As

Publication number Publication date
JP2018515792A (en) 2018-06-14
TWI631331B (en) 2018-08-01
US20160318018A1 (en) 2016-11-03
CN107709990A (en) 2018-02-16
US20160320332A1 (en) 2016-11-03
US10562027B2 (en) 2020-02-18
TWI635907B (en) 2018-09-21
TW201706598A (en) 2017-02-16
WO2016173542A1 (en) 2016-11-03
TW201711750A (en) 2017-04-01
CN107850564A (en) 2018-03-27
US9884320B2 (en) 2018-02-06
EP3274700A4 (en) 2018-10-03
WO2016173547A1 (en) 2016-11-03
EP3274700A1 (en) 2018-01-31

Similar Documents

Publication Publication Date Title
CN107850564B (en) System and method for being detected in ion fluid
Hashemi et al. Ultra-sensitive viral glycoprotein detection NanoSystem toward accurate tracing SARS-CoV-2 in biological/non-biological media
CN110337586B (en) Analyte detector for detecting at least one analyte in at least one fluid sample
Koncki Recent developments in potentiometric biosensors for biomedical analysis
Guan et al. Highly specific and sensitive non-enzymatic determination of uric acid in serum and urine by extended gate field effect transistor sensors
Malon et al. Potentiometry at trace levels in confined samples: ion-selective electrodes with subfemtomole detection limits
Liu et al. Connecting biology to electronics: Molecular communication via redox modality
Alatraktchi et al. Electrochemical sensing of biomarker for diagnostics of bacteria-specific infections
Soldatkin et al. Creatinine sensitive biosensor based on ISFETs and creatinine deiminase immobilised in BSA membrane
Viet et al. Gold-linked electrochemical immunoassay on single-walled carbon nanotube for highly sensitive detection of human chorionic gonadotropinhormone
Ben-Yoav et al. A whole cell electrochemical biosensor for water genotoxicity bio-detection
Deng et al. Determination of norfloxacin in human urine by capillary electrophoresis with electrochemiluminescence detection
JP4751302B2 (en) Potential difference sensor and analytical element
Pormsila et al. Capillary electrophoresis with contactless conductivity detection for uric acid determination in biological fluids
Santarino et al. Protein reducing agents dithiothreitol and tris (2-carboxyethyl) phosphine anodic oxidation
Chen et al. A one-step electrochemical sensor for rapid detection of potassium ion based on structure-switching aptamer
Thiruppathi et al. A disposable electrochemical sensor designed to estimate glycated hemoglobin (HbA1c) level in whole blood
US8702957B2 (en) Electrochemical detection of silica species
Wang et al. Selective glucose detection based on the concept of electrochemical depletion of electroactive species in diffusion layer
CN105784814A (en) Sensor based on concentration cell principle
Gardner et al. Development of a microelectrode array sensing platform for combination electrochemical and spectrochemical aqueous ion testing
Sołoducho et al. Electrochemical and optical biosensors in medical applications
Garg et al. Current advancement and progress in BioFET: a review
CN105675876A (en) Ficolin-3 electrochemical immunosensor and preparation and application thereof
Chen et al. Highly sensitive detection of Brucella in milk by cysteamine functionalized nanogold/4-Mercaptobenzoic acid electrochemical biosensor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant